Cryptococcal meningitis (CM) remains a major cause of HIV-related mortality in Africa. Successful management of Cryptococcus in resource-limited areas is often hindered by unsatisfactory or unavailable antifungal regimens. In these settings, treatment failure and relapse are common. Furthermore, widespread availability of ART has led to changes in the meningitis epidemiology in Africa. Persons with cryptococcal meningitis now have more complex disease presentations, with 40-50% presenting while receiving ART. Large knowledge gaps exist in the diagnosis and management of increasing proportions of complex patients, in particular those developing cryptococcal meningitis shortly after initiating ART, second episodes due to paradoxical immune reconstitution inflammatory syndrome (IRIS) with sterile CSF, or second episodes of culture-positive relapse. This mentored international research project is a prospective cohort study of HIV-infected Africans with Cryptococcus in Uganda. The candidate will determine if persons who develop cryptococcal meningitis while already receiving ART will have worse outcomes compared to ART-nave persons in a resource-limited area. The candidate will evaluate whether differential outcomes based on ART status are dependent on expression of biomarkers in cerebrospinal fluid (CSF). Specifically, the candidate will assess whether persons receiving effective ART will have inflammatory patterns of biomarker expression in CSF. Finally, in cases of recurrent symptomatic meningitis, the candidate will evaluate the role of novel laboratory techniques and biomarkers as more sensitive indicators of infection for rapid differentiation of paradoxical IRIS from culture-positive relapse. Dr. Rhein's long-term career goal is to become an independent translational global health researcher who bridges the gap between basic science and clinical research, moving basic science concepts to clinical application in resource-limited settings. During his training to date, Dr. Rhein has spent 4 years on the ground in Kampala, Uganda working on cryptococcal meningitis research. This K01 award will provide for mentored career development using a combination of coursework to supplement current knowledge gaps and practical mentored-research experience to build a strong foundation of laboratory research skills in HIV immunology and CNS pathogenesis. The award will build upon existing international collaborations and help the candidate develop experience in clinical trial design and implementation in an international setting.